1. Technical Field
The present invention generally relates to an improved process for the preparation of pyrimidine derivatives such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) inhibitors and their intermediates. More specifically, the present invention relates to an improved process for the preparation of rosuvastatin and its intermediates using Wittig reagents.
2. Description of the Related Art
The present invention is directed to an improved process for the preparation of pyrimidine derivatives such as rosuvastatin (also known as bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]). Rosuvastatin has the following structural formula I:
Generally, rosuvastatin is a synthetic lipid-lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoA Reductase inhibitor). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. HMG-CoA reductase inhibitors are commonly referred to as “statins.” Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Rosuvastatin is used in the treatment of hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type IIa and IIb). Rosuvastatin calcium is sold under the brand name CRESTOR®.
U.S. Pat. No. 5,260,440 to Hirai et al. discloses pyrimidine derivatives such as rosuvastatin, its calcium salt (2:1) and its lactone form. The '440 patent also discloses a process for the preparation of pyrimidine derivatives in a four step reaction scheme.
The disadvantages of the prior art include multiple steps resulting in difficult preparations, the use of expensive reagents, reagents that are difficult to use on a commercial scale, the use of low temperatures that make the process more difficult to perform, and time consuming and expensive techniques for purification.
Accordingly, there remains a need for an improved process for the preparation of pyrimidine derivatives such as rosuvastatin that eliminates and reduces the problems of the prior art on a commercial scale in a convenient and cost efficient manner.